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4m12: Difference between revisions

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== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[4m12]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4M12 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4M12 FirstGlance]. <br>
<table><tr><td colspan='2'>[[4m12]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4M12 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4M12 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1YZ:4-(CARBAMOYLAMINO)-1-(7-ETHOXYNAPHTHALEN-1-YL)-1H-PYRAZOLE-3-CARBOXAMIDE'>1YZ</scene></td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.15&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1YZ:4-(CARBAMOYLAMINO)-1-(7-ETHOXYNAPHTHALEN-1-YL)-1H-PYRAZOLE-3-CARBOXAMIDE'>1YZ</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4m12 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4m12 OCA], [https://pdbe.org/4m12 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4m12 RCSB], [https://www.ebi.ac.uk/pdbsum/4m12 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4m12 ProSAT]</span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4m12 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4m12 OCA], [https://pdbe.org/4m12 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4m12 RCSB], [https://www.ebi.ac.uk/pdbsum/4m12 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4m12 ProSAT]</span></td></tr>
</table>
</table>
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== Function ==
== Function ==
[https://www.uniprot.org/uniprot/ITK_HUMAN ITK_HUMAN] Tyrosine kinase that plays an essential role in regulation of the adaptive immune response. Regulates the development, function and differentiation of conventional T-cells and nonconventional NKT-cells. When antigen presenting cells (APC) activate T-cell receptor (TCR), a series of phosphorylation lead to the recruitment of ITK to the cell membrane, in the vicinity of the stimulated TCR receptor, where it is phosphorylated by LCK. Phosphorylation leads to ITK autophosphorylation and full activation. Once activated, phosphorylates PLCG1, leading to the activation of this lipase and subsequent cleavage of its substrates. In turn, the endoplasmic reticulum releases calcium in the cytoplasm and the nuclear activator of activated T-cells (NFAT) translocates into the nucleus to perform its transcriptional duty. Phosphorylates 2 essential adapter proteins: the linker for activation of T-cells/LAT protein and LCP2. Then, a large number of signaling molecules such as VAV1 are recruited and ultimately lead to lymphokine production, T-cell proliferation and differentiation.<ref>PMID:12186560</ref> <ref>PMID:12682224</ref> <ref>PMID:21725281</ref>  
[https://www.uniprot.org/uniprot/ITK_HUMAN ITK_HUMAN] Tyrosine kinase that plays an essential role in regulation of the adaptive immune response. Regulates the development, function and differentiation of conventional T-cells and nonconventional NKT-cells. When antigen presenting cells (APC) activate T-cell receptor (TCR), a series of phosphorylation lead to the recruitment of ITK to the cell membrane, in the vicinity of the stimulated TCR receptor, where it is phosphorylated by LCK. Phosphorylation leads to ITK autophosphorylation and full activation. Once activated, phosphorylates PLCG1, leading to the activation of this lipase and subsequent cleavage of its substrates. In turn, the endoplasmic reticulum releases calcium in the cytoplasm and the nuclear activator of activated T-cells (NFAT) translocates into the nucleus to perform its transcriptional duty. Phosphorylates 2 essential adapter proteins: the linker for activation of T-cells/LAT protein and LCP2. Then, a large number of signaling molecules such as VAV1 are recruited and ultimately lead to lymphokine production, T-cell proliferation and differentiation.<ref>PMID:12186560</ref> <ref>PMID:12682224</ref> <ref>PMID:21725281</ref>  
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== Publication Abstract from PubMed ==
IL-2-induced T cell kinase (ITK) is a critical component of signal transduction in T cells and has a well-validated role in their proliferation, cytokine release and chemotaxis. ITK is an attractive target for the treatment of T-cell mediated inflammatory diseases. Here we describe the discovery of kinase inhibitors that preferentially bind to an allosteric pocket of ITK. The novel ITK allosteric site was characterized by NMR, surface plasmon resonance, isothermal titration calorimetry, enzymology, and X-ray crystallography. Initial screening hits bound to both the allosteric pocket and the ATP site. Successful lead optimization was achieved by improving the contribution of the allosteric component to the overall inhibition. NMR competition experiments demonstrated that the dual-site binders showed higher affinity for the allosteric site compared to the ATP site. Moreover, an optimized inhibitor displayed non-competitive inhibition with respect to ATP as shown by steady-state enzyme kinetics. The activity of the isolated kinase domain and auto-activation of the full-length enzyme were inhibited with similar potency. However, inhibition of the activated full-length enzyme was weaker, presumably because the allosteric site is altered when ITK becomes activated. An optimized lead showed exquisite kinome selectivity and is efficacious in human whole blood and proximal cell-based assays.
Selectively targeting an inactive conformation of IL-2-induced T cell kinase by allosteric inhibitors.,Han S, Czerwinski RM, Caspers NL, Limburg DC, Ding W, Wang H, Ohren JF, Rajamohan F, McLellan TJ, Unwalla R, Choi C, Parikh MD, Seth N, Edmonds J, Phillips C, Shakya S, Li X, Spaulding V, Hughes S, Cook A, Robinson C, Mathias JP, Navratilova I, Medley QG, Anderson DR, Kurumbail RG, Aulabaugh A Biochem J. 2014 Mar 4. PMID:24593284<ref>PMID:24593284</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 4m12" style="background-color:#fffaf0;"></div>


==See Also==
==See Also==

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